Transdermal Therapeutic System For Administering Rivastigmine Or Derivatives Thereof

ABSTRACT

The present invention relates to a transdermal therapeutic system for administering an active substance through the skin, comprising:
         a) a cover layer,   b) a reservoir present on the cover layer, comprising a polymer matrix comprising the active substance,   c) an adhesive layer present on the reservoir comprising a contact adhesive, and   d) a removable layer present on the adhesive layer,
 
the active substance being rivastigmine, a physiologically compatible salt, hydrate, solvate or derivative thereof,
 
characterized in that the polymer matrix of the reservoir comprises neither hydroxyl groups nor carboxyl groups.

This application is a continuation of copending U.S. Ser. No.13/518,006, filed Jun. 21, 2012, which is a national stage applicationof International Application No. PCT/EP2010/069654, filed 14 Dec. 2010,which claims priority from European Patent Application No. 09180413.8,filed 22 Dec. 2009, and from European Patent Application No. 10154648.9,filed 25 Feb. 2010, from which applications priority is claimed, andwhich all are incorporated herein by reference.

The present invention relates to a system for the transdermaladministration of rivastigmine or a physiologically compatible salt,hydrate, solvate or derivative thereof for therapeutic purposes.

Rivastigmine is the phenyl carbamate(S)—N-ethyl-3-[(1-dimethylamino)ethyl]-N-methyl-phenyl-carbamate offormula I.

It is a cholinesterase inhibitor acting on the central nervous systemand, therefore, an active substance for treating Alzheimer's andParkinson's dementia.

Rivastigmine can be present as a free base, but also as an acid additionsalt, hydrate, solvate or another derivative. Unless indicatedotherwise, said derivatives shall be comprised in the designation“rivastigmine” for purposes of the present invention.

A preferred administration form of rivastigmine is the percutaneousadministration route by means of a transdermal therapeutic system,meaning a transdermal patch. Typically, a transdermal patch is aself-adhesive bandage that contains the active substance to beadministered. These bandages can have different shapes and sizes. Thesimplest type is an adhesive monolith that comprises a supply of activesubstance (reservoir) on a carrier (cover layer). The reservoir istypically constituted of the active substance in a pharmaceuticallyacceptable, pressure-sensitive adhesive and is in contact with thesurface of the skin, whereby the active substance is released into thebody of the patient by means of transdermal diffusion.

More complex patches are multi-laminates or patches with an activesubstance supply that can have a further adhesive layer disposed betweenthe reservoir and the skin.

One administration form of rivastigmine by means of a transdermal patchhas been specified previously in the basic patent on rivastigmine, whichis GB 2203040. The transdermal patch disclosed therein consists of acover layer and a layer constituting the reservoir. Aside from theactive substance rivastigmine, the reservoir contains a hydrophilicpolymer, non-swelling acrylate polymer and an emollient.

After the publication of GB 2203040, further transdermal therapeuticsystems (TTS) containing, among others, rivastigmine as activesubstance, have been developed and described. WO 02/03969 specifies aTTS in which the matrix layer comprising the active substance(reservoir) also contains, in addition, highly dispersed silicon dioxideto increase skin permeation.

In DE 199 18 106, the reservoir contains a contact-adhesive polymer thatincludes acrylic acid or methacrylic acid units of a defined carboxylgroup content, indented to improve the absorbency of water as well asthe tolerance of acidic polyacrylic contact adhesives relative tomoisture.

WO 2007/064407 A1 discloses a TTS having a silicone-based adhesive layerintended to improve the adhesive properties, tolerance and safety ofrivastigmine therapy. According to WO 2007/064407 A1, it is especiallypreferred for the reservoir layer to contain an antioxidant (page 7,paragraph 4). Correspondingly, all formulations in the examples containthe antioxidant vitamin E. The trade product Durotak® 387-2353 that isused therein is a polyacrylate with carboxyl groups. WO 2007/064407 A1provides that the reservoir layer also include different substances toimprove penetration such as, for example, glycerin, fatty acids (page 7,paragraph 5). Most of the time, these substances contain free hydroxylor carboxyl groups, which are thus also present in the polymer matrix ofthe reservoir layer. WO 2007/064407 A1 does not specifically address thestability of rivastigmine. In particular, WO 2007/064407 A1 does notteach how to select certain polymers for the polymer matrix of thereservoir layer to prevent the rivastigmine from being broken down.

US 2008/0044461 A1 discloses TTS formulations with donepezil (seeexamples). Rivastigmine is mentioned as well (Claim 7). US 2008/0044461A1 does not disclose an active-substance layer having a polymer matrix.Rather, the release mechanism is controlled by means of a membrane(so-called membrane patches), not by a polymer backbone that has theactive substance embedded therein (so-called matrix patch). Moreover,one essential characteristic of US 2008/0044461 A1 provides that thereservoir can contains a gelatinizing agent and a permeation enhancer(see Claim 1). Alcohols are used as permeation enhancers (see [0053]).Cellulose polymers are used as gelatinizing agents (see [0055]).Therefore, the permeation enhancers as well as the gelatinizing agentsare compounds with free hydroxyl groups that are present in the TTS inthe reservoir layer.

US 2007/0259028 A1 discloses TTS formulations with donepezil (seeexamples). Rivastigmine is mentioned as well (Claim 3). One essentialcharacteristic of US 2007/0259028 A1 provides that the reservoir layercontain a polyvalent alcohol such as, for example, glycerin. Accordingto US 2007/0259028 A1, free hydroxyl groups are necessarily present inthe polymer matrix of the reservoir layer.

US 2004/0086552 A1 discloses TTS formulations with an active substancethat can be selected from a very long list (see [0070] to [0095]).Disclosed are matrix patches as well as “membrane patches” (see [0057]and/or [0058]). Regarding matrix patches, US 2004/0086552 A1 does notteach selecting certain polymers for the matrix to stabilize the activesubstance.

U.S. Pat. No. 6,689,379 B1 discloses TTS formulations having a specialadhesive layer. Rivastigmine is also mentioned as a possible activesubstance. Preferably, the active-substance layer is to contain acompound with hydroxyl groups, see claim 10. U.S. Pat. No. 6,689,379 B1does not teach selecting certain polymers for the polymer matrix of thereservoir layer to prevent the rivastigmine from breaking down.

However, patent EP 1 047 409, on the other hand, reports a generalproblem associated with the administration of rivastigmine by means of aTTS. It was found that the active substance tends to degrade especiallyin the presence of oxygen. According to EP 1 047 409, in the transdermalcomposition that is disclosed in GB 2203040, rivastigmine degradesdespite the formation of a closed polymer matrix surrounding the activesubstance and air-tight packaging of the composition. EP 1 047 409resolves the problem of the poor stability of rivastigmine by adding anantioxidant to the pharmaceutical composition.

Therefore, it is the object of the present invention to providetherapeutic compositions containing rivastigmine for transdermaladministration that demonstrate adequate stability even without theaddition of antioxidants.

Surprisingly, it was found that rivastigmine in transdermal patches hasadequate stability if the polymer matrix of the reservoir containsneither hydroxyl groups nor carboxyl groups. The present invention isbased, among other aspects, on selecting special polymers for thepolymer matrix to thereby prevent and/or minimize the break-down ofrivastigmine.

The present invention, correspondingly, provides a TTS that demonstratesadequate stability and contains rivastigmine, as well as a method forpreparing the same. Moreover, the invention envisions the use ofpolymers or copolymers, which contain neither hydroxyl groups norcarboxyl groups, inside a TTS containing rivastigmine, as well as a TTSfor treating Alzheimer's and Parkinson's dementia.

Therefore, a first aspect of the invention consists in providing a TTSfor administering rivastigmine comprising the following components:

-   -   a) a cover layer,    -   b) a reservoir present on the cover layer, comprising a polymer        matrix with the embedded active substance, and wherein the        active substance is rivastigmine or a physiologically compatible        salt, hydrate, solvate or derivatives thereof,    -   c) an adhesive layer on the reservoir comprising a first        polyisobutylene polymer of a mean molecular weight between        30,000 g/mol and 100,000 g/mol and a second polyisobutylene        polymer of a mean molecular weight between 300,000 g/mol and        500,000 g/mol, and    -   d) a removable layer present on the adhesive layer characterized        in that the polymer matrix of the reservoir includes neither        hydroxyl groups nor carboxyl groups.

A second aspect of the invention is a TTS for administering rivastigminecomprising the following components:

-   -   a) a cover layer,    -   b) a reservoir present on the cover layer, comprising a polymer        matrix comprising the embedded active substance,    -   c) an adhesive layer present on the reservoir comprising a        contact adhesive, and    -   d) a removable layer present on the adhesive layer,        and wherein the active substance is rivastigmine or a        physiologically compatible salt, hydrate, solvate or derivative        thereof, and wherein the polymer matrix of the reservoir        includes neither hydroxyl groups nor carboxyl groups.

A “polymer matrix” is a solid or semi-solid composition having athree-dimensional structure comprising a polymer or polymer mixture. Thepolymer matrix is also referred to as the polymer backbone because thepolymer or polymer mixture typically provides the three-dimensionalbackbone structure. The polymer matrix can also have further substancessuch as, for example, an active substance that is embedded therein.Preferably, the active substance is evenly distributed throughout thepolymer matrix. A person skilled in the art will be familiar withso-called “matrix patches” in which the polymer matrix is the controlmechanism for the release of the active substance.

In the TTS according to the invention, the active substance rivastigminedemonstrates adequate stability. “Adequate stability” herein means thatcontaminations of the active substance after one month of storage at 40°C. and 75% relative humidity are overall no more than 1 weight %,preferably no more than 0.5 weight %, in relation to the desiredactive-substance content in the formulation. Contaminations of theactive substance in the formulation are defined herein as degradationproducts of the active substance rivastigmine and any contaminationsthat entered the formulation together with the active substance (forexample, intermediate product traces from the preparation of the activesubstance).

The stability and/or the quantity of contaminants can be detected asdescribed in the example. Preferably, the total content of degradationproducts/contaminations after three months of storage at 40° C. and 75%relative humidity should be 1 weight % or less, more preferably lessthan 0.6 weight %. It is also preferred that the total content of thedegradation products/contaminations after six months of storage at 40°C. and 75% relative humidity is less than 1 weight %. It is furtherpreferred that the total content of contaminations after one month ofstorage at 25° C. and 60% relative humidity is less than 0.25 weight %.Also preferred, furthermore, is that the total content of contaminationsafter three and after six months of storage at 25° C. and 60% relativehumidity is less than 0.5 weight %. The information as to “weight %” ofcontaminations always refers to the desired active-substance content inthe formulation, unless indicated otherwise.

The length of application of the TTS according to the invention is,preferably, approximately 24 hours. A longer application is possible.

Preferably, an antioxidant is not be added to any component of the TTS.However, it is quite possible for antioxidants to be available in thepresent invention, provided they do not negatively impact the mode ofaction of the TTS. To be noted herein is the fact that antioxidants arenot necessary to stabilize rivastigmine according to the presentinvention. Antioxidants could, however, also be used for other purposesthan the above purpose in the context of the TTS according to theinvention. Therefore, it is possible, although not preferred, for theTTS according to the invention to contain antioxidants.

An “antioxidant” within the meaning of the present invention is apharmaceutically compatible compound or composition that decelerates,inhibits, interrupts and/or stops oxidation processes. Antioxidantsinclude, in particular, the following substances: tocopherols and theesters thereof, sesamol of sesame oil, coniferyl benzoate of benzoinresin, nordihydroguaietic resin and nordihydroguaiaretic acid (NDGA),gallates (among others, methyl, ethyl, propyl, amyl, butyl, laurylgallates), butylated hydroxyanisole (BHA/BHT, also butyl-p-cresol);ascorbic acid and salts and esters thereof (for example, acorbylpalmitate), erythorbinic acid (isoascorbinic acid) and salts and estersthereof, monothioglycerol, sodium formaldehyde sulfoxylate, sodiummetabisulfite, sodium bisulfite, sodium sulfite, potassiummetabisulfite, butylated hydroxyanisole, butylated hydroxytoluene (BHT),propionic acid. Typical antioxidants are tocopherol such as, forexample, α-tocopherol and the esters thereof, butylated hydroxytolueneand butylated hydroxyanisole. The terms “tocopherol” also includesesters of tocopherol. A known tocopherol is α-tocopherol. The term“α-tocopherol” includes esters of α-tocopherol (for example,α-tocopherol acetate).

Preferably, the reservoir, more preferred the entire TTS, does notcontain any tocopherol. In a further embodied example, the reservoir,preferably the entire TTS, does not contain any tocopherol and nor anybutylated hydroxyanisole (BHA/BHT, also butyl-p-cresol). In a furtherembodied example, the reservoir, preferably the entire TTS, does notcontain any tocopherol, nor any butylated hydroxyanisole, nor anybutylated hydroxytoluene. In a special embodied example, the reservoir,preferably the entire the TTS, does not contain any of the followingantioxidants: tocopherol and the esters thereof, sesamol of sesame oil,coniferyl benzoate of benzoin resin, nordihydroguaietic resin andnordihydroguaiaretic acid (NDGA), gallates (among others, methyl, ethyl,propyl, amyl, butyl, lauryl gallates), butylated hydroxdyanisole(BHA/BHT, also butyl-p-cresol); ascorbinic acid and salts thereof,ascorbyl palmitate, erythorbinic acid (isoascorbinic acid) and salts andesters thereof, monothioglycerol, sodium formaldehyde sulfoxylate,sodium metabisulfite, sodium bisulfite, sodium sulfite, potassiummetabisulfite, butylated hydroxyanisole, butylated hydroxytoluene,propionic acid. In special preferred example, the reservoir, morepreferred the entire TTS, does not contain any antioxidants.

The antioxidant quantity in the TTS of the present invention is usuallyless than 1 weight % or less than 0.1 weight-%, more preferred less than0.05 weight-%, most preferred less than 0.01 weight-%, respectively inrelation to the weight of the total formulation (without cover layer andremovable layer).

The structure of the TTS according to the invention comprises multiplelayers. A cover layers is located at the end of the TTS that comes tolie opposite to the skin during application. The reservoir is located onthe side of the cover layer that is directed toward the human skinduring use. In addition, the adhesive layer is located on the sidedirected toward the human skin during use. Before the application, aremovable layer is located on the side that is directed toward the humanskin and that is pulled off immediately before use of the TTS.

The area of the TTS according to the invention is not subject to anyspecial limitations. Usually the area is 5 to 30 cm² in size; however,larger or smaller sizes are possible.

The area of the cover layer of the TTS according to the inventioncorresponds in one embodied example at least to the area of thereservoir and/or the adhesive layer. However, it can be larger than thearea of the reservoir, whereby the reservoir is fully covered with thecover layer extending even beyond the edge of the reservoir. However, insuch an embodied example, either the area of the adhesive layer shouldbe equal to the area of the cover layer, or the layer of the cover layerthat is directed toward the skin should have a further adhesive layer inorder to ensure that, during the application, the entire surface of theTTS that is directed toward the skin adheres to the skin. In anotherembodied example, the cover layer is somewhat smaller than the area ofthe reservoir.

Reservoir

The reservoir layer of the TTS according to the invention has the activesubstance rivastigmine embedded in a polymer matrix. According to thisaspect of the invention, the polymer matrix consists exclusively ofpolymers or copolymers that do not include any hydroxyl groups, nor anycarboxyl groups. Preferred polymers or copolymers without functionalgroups constituting the polymer matrix are certain polyacrylates,acrylate-vinyl acetate copolymers, polyisobutylene and styrene-butadienecopolymers than can be present individually or as a mixture.

Possible for use as expedient polyacrylates, essentially not containingany free functional groups, are polymers (homopolymers, copolymers andblock copolymers) on the basis of acrylic acid esters and/or methacrylicacid esters. Suitable monomer alternatives for the preparation ofexpedient polyacrylates are, in particular, n-butyl acrylate, n-butylmethacrylat, ethyl acrylate, 2-ethylhexyl acrylate, ethyl methacrylate,methyl acrylate, methyl methacrylate, tert-butyl acrylate, sec-butylacrylate, tert-butyl methacrylate, cyclohexyl methacrylate, 2-ethylhexylmethacrylate, isobornyl methacrylate, isobutyl methacrylate, isopropylacrylate, isopropyl methacrylate and mixtures of these monomers. Thesemonomers are esters of acrylic and/or methacrylic acid carrying linear,branched or cyclic aliphatic C₁-C₁₂ substituents, without having anyother free functional groups. Vinyl acetate, as well, can be used as aco-monomer together with at least one of these monomers for thepreparation of the polyacrylate.

Preferably, the polymer matrix consists of one or several polyacrylatesthat essentially do not contain any free functional groups. Morepreferred, the polymer matrix consists of polyacrylates that wereprepared by polymerizing acrylic acid esters and/or methacrylic acidesters. In a special embodied example, the polymer matrix consists ofpolyacrylates that were obtained by polymerizing acrylic acid estersand/or methacrylic acid esters, and wherein the acrylic acid estersand/or methacrylic acid esters are selected from the group consisting ofn-butyl acrylate, n-butyl methacrylate, ethyl acrylate, 2-ethylhexylacrylate, ethyl methacrylate, methyl acrylate, methyl methacrylate,tert-butyl acrylate, sec-butyl acrylate, tert-butyl methacrylate,cyclohexyl methacrylate, 2-ethylhexyl methacrylate, isobornylmethacrylate, isobutyl methacrylate, isopropyl acrylate, isopropylmethacrylate and mixtures thereof. In another embodied example, thepolymer matrix consists essentially of polyacrylates that were preparedby copolymerizing acrylic acid esters and/or methacrylic acid esterswith vinyl acetate, and wherein the acrylic acid esters and/ormethacrylic acid esters were selected from the group consisting ofn-butyl acrylate, n-butyl methacrylate, ethyl acrylate, 2-ethylhexylacrylate, ethyl methacrylate, methyl acrylate, methyl methacrylate,tert-butyl acrylate, sec-butyl acrylate, tert-butyl methacrylate,cyclohexyl methacrylate, 2-ethylhexyl methacrylate, isobornylmethacrylate, isobutyl methacrylate, isopropyl acrylate, isopropylmethacrylate and mixtures thereof.

Especially preferred are as follows: the acrylate-vinyl acetatecopolymer Duro-Tak® 87-4098, prepared, respectively, at approximately50% of starting monomers 2-ethylhexyl acrylate and vinyl acetate; theacrylate Duro-Tak® 87-9088 (also an acrylate polymer without functionalgroups) available from the company Henkel. In a special embodiedexample, the acrylate Duro-Tak® 87-900A or Duro-Tak® 87-9301 is used forthe polymer matrix.

The total proportion of monomers containing free hydroxyl groups or freecarboxyl groups (for example, acrylic acid, methacrylic acid and estersof acrylic acid and/or methacrylic acid carrying functional groups, inparticular esters containing hydroxyl groups) is less than 1 weight %,preferably less than 0.5 weight %, more preferred less than 0.2 weight%, in relation to the monomer mixture from which the polymer matrix isprepared. In one special embodied example, the total proportion of thesemonomers is less than 0.1 weight %. In one special embodied example, themonomer mixture does not contain any free hydroxyl groups, nor any freecarboxyl groups.

A TTS that contains polyacrylates as polymer matrix withactive-substance content being free of hydroxyl groups and carboxylgroups has been described previously in WO 03/017988 A1; however, not inconnection with rivastigmine as active substance. The task to beachieved as specified in WO 03/017988 was to describe a remedy for thedisadvantage of poor utilization of the active substance within a TTS.According to said disclosure, this object was achieved by polymermatrixes that were ideally completely free of hydroxyl groups orcarboxyl groups. The active substance rivastigmine is not mentioned inthis specification, nor any action for improving the stability ofrivastigmine.

In one embodied example of the invention, the reservoir is essentiallywithout polymers or copolymers that contain any free hydroxyl groups orfree carboxyl groups. Preferably, the reservoir contains neither anyfree hydroxyl groups nor any free carboxyl groups. More preferred, thereservoir essentially does not contain any free amino groups, nor anyfree hydroxyl groups, nor any free carboxyl groups. In a specialembodied example, the adhesive layer is essentially also free ofpolymers or copolymers containing any free hydroxyl groups or any freecarboxyl groups. Preferably, the adhesive layer does not contain anyfree hydroxyl groups, nor any free carboxyl groups. More preferred, theadhesive layer does not contain any free amino groups, nor any freehydroxyl groups, nor any free carboxyl groups.

Preferably, the reservoir contains 20 to 40 weight % rivastigmine and 60to 80 weight % polymer matrix in relation to the total weight of thereservoir layer. In a special embodied example of the TTS, the reservoircontains 25 weight % rivastigmine and 75 weight % polymer matrix.Preferably, the reservoir has no further components in addition to theactive substance and the polymer matrix. However, it is possible forfurther additives known from the prior art to be present in thereservoir. For example, emollients or gelatinizing agents can also bepresent in the reservoir.

The absolute quantity of rivastigmine depends on different factors, inparticular the size of the TSS to be used, the weight per unit area andthe concentration of the active substance within the reservoir. Theweights per unit area of dried reservoir matrix are, preferably, in therange of 20 to 100 g/m², more preferred in a range of 25 to 80 g/m², andeven more preferred in a range of 30 to 70 g/m². The reservoir can havea thickness (dry thickness) in the range of 20 to 400 μm, or 30 to 200μm, or 40 to 100 μm. Other thicknesses than those mentioned above arealso possible.

Adhesive Layer

The adhesive layer of the TTS according to the invention contains acontact adhesive, preferably consisting of polyisobutylene.Polyisobutylene is a pressure-sensitive contact adhesive that does notset and, therefore, maintains its adhesive properties over long periodsof time. Preferably, polyisobutylenes having differing mean molecularweights are used by way of a mixture. Polyisobutylene is availble indifferent mean molecular weights. The term “mean molecular weight” inconnection with polyisobutylene in the context of the presentapplication refers to the so-called viscosity-average molecular weight,M_(V). The viscosity-average molecular weight M_(V) is determined fromthe solution viscosity of a solution of polyisobutylene in isooctane at20° C. The measuring instrument is an Ubbelohde's viscometer. Theaverage viscosity is calculated using the formula below:

$M_{v} = {\underset{\_}{0.65}\sqrt{\frac{J_{o} \times 10^{2}}{3.06}}}$

The Staudinger index J_(o) of intrinsic viscosity that is necessary forthe determination of the viscosity-average molecular weight M_(V) isobtained according to the Schulz-Blaschke relationship from the measuredspecific viscosity η_(sp) and the concentration of the solution.

J _(o)=η_(sp) /C(1+0.31×η_(sp))cm³/g (Schulze-Blaschke relationship)

The specific viscosity η_(SP)=t/t₀−1, wherein t and t₀ are the flow timeof the solution and/or solvent (with Hagenbach-Couette correction,respectively), and c is the concentration of the solution in g/cm³. Ifnecessary, regulation DIN 53728 can be used as well in a supplementaryfashion.

Expedient mean molecular weights M_(V) of polyisobutylene are, forexample, in the range from approximately 40,000 g/mol to approximately4,000,000 g/mol. One preferred mixture consists of (1) polyisobutylenehaving a mean molecular weight M_(V) of approximately 40,000 g/mol (forexample, Oppanol® B10, available from the company BASF) and (2)polyisobutylene having a mean molecular weight M_(V) of aboveapproximately 1,000,000 g/mol (for example, Oppanol® B100, availablefrom BASF, of a mean molecular weight M_(V) of approximately 1,110,000g/mol). It is within the expert knowledge of a person skilled in the artto mix the different molecular weights at expedient ratios in order toobtain the desired properties for the adhesive layer.

The polyisobutylene in the adhesive layer can include a molecular weightdistribution having a first relative maximum between 30,000 g/mol and100,000 g/mol and a second relative maximum between 300,000 g/mol and500,000 g/mol. More preferred, the first relative maximum is between35,000 g/mol and 50,000 g/mol and the second relative maximum,independently thereof, between 350,000 g/mol and 450,000 g/mol. Mostpreferred, the first relative maximum is approximately at 40,000 g/moland, independently thereof, the second relative maximum is approximatelyat 400,000 g/mol.

The polyisobutylene mixture of the contact adhesive can be obtained bymixing a first polyisobutylene polymer of a mean molecular weight M_(V)between 30,000 g/mol and 100,000 g/mol with a second polyisobutylenepolymer of a mean molecular weight M_(V) of between 300,000 g/mol and500,000 g/mol. The first polyisobutylene polymer, preferably, has a meanmolecular weight M_(V) in the range between 35,000 g/mol and 50,000g/mol, most preferably a value of approximately 40,000 g/mol. The secondpolyisobutylene polymer, preferably, has a mean molecular weight M_(V)in the range between 350,000 g/mol and 450,000 g/mol, most preferably avalue of approximately 400,000 g/mol.

The most preferred mixture is that of (1) polyisobutylene of a meanmolecular weight M_(V) of approximately 40,000 g/mol (for example,Oppanol® B10 SFN, available from BASF) and (2) polyisobutylene of a meanmolecular weight M_(V) of approximately 400,000 g/mol (for example,Oppanol® B50 SF, available from BASF).

The proportions at which the two polyisobutylene polymers are presentwithin the mixture can vary. The weight ratio of the firstpolyisobutylene polymer relative to the second polyisobutylene polymerin the mixture can be from 10:1 to 1:10, preferably it is 2:1 to 1:2;the most preferred weight ratio is 4:6. In a special embodied example,the polyisobutylene polymer of the contact adhesive consists of fourweight parts Oppanol® B10 (for example, Oppanol® B10 SFN) and six weightparts Oppanol® B50SF.

The contact adhesive is present in the adhesive layer according to theinvention at a quantity that is in the range of 40 to 100 weight %,preferably 50 to 90 weight %, more preferred at 55 to 80 weight % andeven more preferred 60 to 69.9 weight % in relation to the total weightof the adhesive layer.

The thickness of the adhesive layer (dry thickness) is not subject toany special limitations. It can be in the range of approximately 10 to300 μm or in the range between 70 to 140 μm. The absolute quantity ofthe adhesive layer can be approximately 10 to 50 g/m² or 20 to 40 g/m²,without being limited thereto.

Preferably, the adhesive layer further contains emollients andgelatinizing agents. Expedient emollients are known from the prior art;preferably, these are mineral oil, neutral oil, paraffin, polybutenes,linseed oil, octyl palmitate, squalene, squalane, silicone oil, isobutylmyristate, isostearyl alcohol and/or oleyl alcohol, especially preferredare mineral oil, neutral oil, polybutenes and/or paraffin. Mineral oilare colorless, clear hydrocarbons. They are obtained from thedistillation fractions of raw oil that boil above approximately 300° C.and are freed of any solid hydrocarbons by cooling. Utilizing expedientfractioning, it is possible to obtain mineral oils that are liquid atbody temperature, meaning approximately 35 to 37° C., while they aresolid at lower temperatures, in particular temperatures below 20° C.Selecting a mineral oil with a melting point of approximately 30 to 35°C. is preferred. Paraffin and mineral oils that are in compliance withthe requirements of Ph. Eur. 6 and/or USP 32-NF 27 are especiallypreferred.

Preferably, the emollient is present in the adhesive layer at a quantityin the range from 0 to 60 weight %, more preferred in the range from 10to 50 weight %, even more preferred in the range of 25 to 39.9 weight %,for example 35 weight %, in relation to the total weight of the adhesivelayer.

The gelatinizing agent is preferably a gelatinizing agent of a particlestructure having on its surface a high concentration of polar groups.The same create correspondingly high interfacial surface tensions thatare in part compensated by agglomeration of the particles into gelskeletons. Correspondingly, the greater the polarity difference betweenthe oils and the surface of the skeleton former, the more solid are thegel skeletons. Preferably, the invention provides for the use of highlydispersed silicone dioxide or pyrogenic silicic acid. The size of theparticles is, preferably, in the nanometer range such as, for example inthe range of 400 to 1500 nm, especially in the range of 500 to 1000 nm.Pyrogenic silicic acid is sold, for example, under the trade nameCAB-O-SIL® and is a known thickening agent for mineral oil. A furtherexample of an expedient gelatinizing agent is bentonite. Also possibleis the use of sodium carbomer that is known in the art as a gelatinizingagent. Preferably, the gelatinizing agent is used at a quantity of 0.1to 4.0 weight %, more preferred at 0.1 to 2.0 weight %, even morepreferred at 0.5 to 2.0 weight %, in relation to the weight of theadhesive layer.

In an especially preferred embodied example of the TTS according to theinvention, the adhesive layer contains 60 to 69.9 weight % contactadhesive, and/or polyisobutylene, and wherein the same, as describedabove, can consist of polyisobutylene mixtures of different molecularweights, 0.1 to 2.0 weight % gelatinizing agent, and/or highly dispersedsilicone dioxide or pyrogenic silicic acid, and 25 to 39.9 weight %emollient, and/or mineral oil, in relation to the total weight of theadhesive layer.

Preferably, the cover layer of the TTS according to the invention is ofan occlusive nature, meaning it closes off the system. In a preferredembodied example, such cover layers can consist of polyolefins,particularly polyethylene, or of polyesters as well polyurethanes.Layers containing several polymers disposed one on top of the other arealso advantageously usable. Expedient materials comprise polyolefin,cellophane, cellulose acetate, ethyl cellulose, emollient-provided vinylacetate-vinyl chloride copolymers, ethylene-vinyl acetate copolymers,polyethylene therephtalate, nylon, polyethylene, polypropylene,polyvinylidene chloride, ethylene-methacrylate copolymers, paper thatcan be coated, if necessary, textile fabrics, aluminum foil andcomposite polymer metal materials. Especially preferred are polyesterfilms, such as polyethylene therephtalate films. The thickness of thebacking can be for example 10 μm to 100 μm, as is common in the priorart such as, for example, approximately 40 μm (nominal thickness). Veryespecially preferred are film-based dressings made of pigmented PE, PETPand aluminum.

According to the invention, a removable layer is located on the adhesivelayer, also referred to as the “release liner.” This removable layer ispreferably manufactured of a polymer material that can be metalized, ifnecessary. Examples of preferably used materials are polyurethanes,polyvinyl acetate, polyvinylidene chloride, polypropylene,polycarbonate, polystyrene, polyethylene, polyethylene therephtalate,polybutylene therephtalate as well as paper that is surface-coated withthe corresponding polymers, if necessary. Preferably, this is aone-sided or two-sided siliconized or fluoropolymer-coated removablelayer. Especially preferred are commonly available fluoropolymer-coatedor siliconized polyester films such as, for example, the one-sided,siliconized trade products Primeliner 100 μm and Perlasic LF 75 μm (bythe companies Loparex, NL and Perlen Converting AG, Switzerland) or theone-sidedly fluoropolymer-coated products such as, for example,ScotchPak 1022 (3M Drug delivery).

An especially preferred embodied example of the TTS according to theinvention is a TTS for administering an active substance through theskin comprising:

-   -   a) a cover layer,    -   b) a reservoir located on the cover layer containing 20 to 30        weight % active substance and 70 to 80% polymer matrix in        relation to the total weight of the reservoirs, and wherein the        polymer matrix consists essentially of an acrylate-vinyl acetate        copolymer without hydroxyl groups and without carboxyl groups,        and wherein the active substance is rivastigmine or a        physiologically compatible salt, hydrate, solvate or derivative        thereof,    -   c) an adhesive layer located on the reservoir that comprises 0.1        to 1 weight % silicone dioxide, 25 to 39.9 weight % of a light        mineral oil (paraffinum perliquidum) and as contact adhesive 60        to 79.9 weight % of a mixture of a polyisobutylene polymer of a        mean molecular weight M_(V) of approximately 40,000 g/mol and a        polyisobutylene polymer of a mean molecular weight M_(V) of        approximately 400,000 g/mol; and    -   d) a removable layer located on the adhesive layer,        and wherein the quantity of antioxidant in the total        formulation, without cover and removable layer, is less than 0.1        weight %, preferably less than 0.01%.

In one special embodied example, the TTS according to the invention doesnot contain an antioxidant that is selected of the group consisting ofvitamin E and esters thereof, butylated hydroxytoluene and butylatedhydroxyanisole.

A third aspect of the present invention is a transdermal therapeuticsystem for administering an active substance through the skincomprising:

-   -   a) a cover layer,    -   b) a reservoir located on the cover layer comprising a polymer        matrix containing the active substance,    -   c) an adhesive layer located on the reservoir comprising a        contact adhesive, and    -   d) a removable layer located on the adhesive layer;        and wherein the active substance is rivastigmine or a        physiologically compatible salt, hydrate, solvate or derivative        thereof, characterized in that the TTS does not contain any        antioxidants.

Preferably, the polymer matrix of the reservoir (of the TTS as set forthin the third aspect according to the invention) contains neitherhydroxyl groups nor carboxyl groups. The embodied examples as describedabove with regard to the first and/or second aspect of the inventionapply correspondingly for the third aspect without any need forreiterating them.

A forth aspect of the present invention consists in providing a methodfor preparing the TTS according to the invention. The method comprises:

-   -   i) preparing a component containing the reservoir made up of the        cover layer and the reservoir, which is located on the side of        the cover layer that is intended as the side to be directed        toward the skin;    -   ii) preparing a component containing the adhesive layer made up        of the removable layer and the adhesive layer located on the        removable layer; and    -   iii) laminating to combine the components from i) and ii) so        that in the end, in the cross-section of the completed TTS, the        cover and removable layers constitute the outermost, opposite        layers.

A preferred embodied example of this method comprises

-   -   i) applying, with drying, if necessary, a film of a composition        constituting the reservoir, if necessary, in form of a solution        or dispersion in an expedient medium to the side of the cover        layer that is to be directed toward the skin and, if necessary,        coating with a siliconized removable film (liner); or applying        and subsequent drying, if necessary, of a film constituting the        composition of the reservoir, if necessary, in form of a        solution or dispersion in an expedient medium, to a siliconized        removable film (liner) and coating with a cover layer;    -   ii) applying, with subsequent drying, if necessary, a film of a        composition constituting the adhesive layer, if necessary, in        the form of a solution or dispersion in an expedient medium, to        the removable layer; and    -   iii) laminating together the components from i) and ii), if        necessary, removing the liner in order for the cover layer and        the removable layer to constitute in the cross-section of the        completed TTS the outermost, opposite layers.

The preparation of a preferred TTS can be achieved by first dispersingand/or dissolving the components for the reservoir, meaning rivastigmineand the matrix-forming polymer and/or copolymer or a mixture thereof, inan organic solvent such as heptane or ethyl acetate (provided thepolymer is not already available in a dissolved form). Thematrix-forming polymer and/or copolymer or the mixture thereof is/areusually already available in a solvent. According to the invention, apolymer and/or copolymer is/are used as defined in connection with theTTS according to the invention above, meaning a polymer and/or copolymerwithout hydroxyl groups and without carboxyl groups. The embodiedexamples of the polymer matrix, which are mentioned above as preferred,apply correspondingly for the method according to the invention. Avolatile organic solvent is preferably used in the preparation of thereservoir. This mixture is then applied in an even layer to the coverlayer and dried. Preferably, to protect it, the component for thereservoir is provided with a film, preferably a siliconized polyesterfilm, which is also referred to as an “intermediate liner” and isapplied to the side of the reservoir that is opposite to the coverlayer. In the alternative, and/or as an equivalent, it is possible toapply the mixture initially to the “intermediate liner” and dry it, andwherein the cover layer is then applied to the side of the reservoirlocated opposite of the “intermediate liner.” The “intermediate liner”is removed shortly before the reservoir component is combined with thecomponent containing the adhesive layer.

The adhesive layer is prepared in a separate work step by dispersing thepolymer mixture constituting the contact adhesive (dissolved in anorganic solvent), preferably polyisobutylene of different mean molecularweights, together with the gelatinizing agent and the emollient in anorganic solvent, such as heptane. However, preferably, the contactadhesive and the emollient are dissolved in an organic solvent and,subsequently, the gelatinizing agent is dispersed in this solution. Thismixture is then applied to the removable film and allowed to dry.

The components obtained in the two method steps are subsequentlylaminated together; specifically, in such a way that the adhesive layeris directly applied to the reservoir. The finished laminated film piecescan afterwards be punched into the desired sizes and packaged.

The organic solvents that are needed for the individual method steps inorder to dissolve the respective components in solution and/or todisperse them are removed by exposing the products to increasingtemperatures, if necessary including the application of a vacuum.

A fifth aspect of the present invention constitutes the use of a polymeror copolymer in the context of a rivastigmine-containing TTS thatincludes neither hydroxyl groups nor carboxyl groups. Preferred arepolyacrylates, acrylate-vinyl acetate copolymers, polyisobutylene andstyrene-butadiene copolymers. According to the invention, these polymersor copolymers represent the polymer matrix in which the active substancerivastigmine is embedded.

Preferably, the use according the invention envisions polyacrylates andpolyacrylate copolymers that are free of any hydroxyl groups and anycarboxyl groups, such as acrylate-vinyl acetate copolymers.

An especially preferred embodied example according to the invention usesacrylate-vinyl acetate copolymer Duro-Tak® 87-4098.

A sixth aspect of the present invention envisions providing the TTSaccording to the invention for treating Alzheimer's and Parkinson'sdementia. The TTS according to the invention is preferably prepared foran application period of approximately 24 hours.

Preferred embodied examples of the TTS according to the invention shallbe described in further detail below; in addition, the properties ofsaid embodied examples in terms of stability shall be determined.

EXAMPLES Examples 1 Preparation of the Different Formulations

Four different batches A-D of TTS formulation containing rivastigminebase were prepared. Acrylate-vinyl acetate copolymer was used asmatrix-forming polymer for the reservoir. An overview of the componentsof the different batches is compiled in Table 1.

TABLE 1 Composition of Batches A to D Batch Composition A 30%rivastigmine base 70% Duro-Tak ® 87-4098 B Reservoir: 30% rivastigminebase 70% Duro-Tak ® 87-4098 Adhesive layer: 30% Klearol ® 1% Cab-O-Sil ®69% Oppanol ® B10/B100 (7/3) C Reservoir: 20% rivastigmine base 80%Duro-Tak ® 87-4098 Adhesive layer: 30% Klearol ® 0.5% Cab-O-Sil ® 69.5%Oppanol ® B10/B100 (7/3) D Reservoir: 25% rivastigmine base 75%Duro-Tak ® 87-4098 Adhesive layer: 30% Klearol ® 1% Cab-O-Sil ® 69%Oppanol ® B10/B100 (7/3)

The components used in the batches can be described in more detail asfollows:

TABLE 2 Component Overview of Formulation Examples A to D Component NameChemical Description Function Duro-Tak ® Acrylate/vinyl acetate Matrix87-4098 copolymer polymer Cab-O-Sil ® Pyrogenic silicone dioxideGelatinizing agent Klearol ® Light mineral oil Emollient Oppanol ® B10Polyisobutylene Contact (M_(w) = 4 × 10⁴ g/mol) adhesive Oppanol ® B100Polyisobutylene Contact (M_(w) = 1.1 × 10⁶ g/mol) adhesive

Preparation Method 1. Preparation of the Reservoir Layer

The acrylate-vinyl acetate adhesive is provided and rivastigmine andethyl acetate are weighed in. Then the components are mixed in asufficient quantity of ethyl acetate by means of an agitator until aspreadable, homogenous coating mass is achieved.

The homogenous coating mass is applied to a siliconized film(“intermediate liner”) as a thin film layer. The matrix film is dried at60° C./20 min and 80° C./5 min, then coated with a cover layer of PET.

2. Preparation of the Adhesive Layer and the Total Laminate

The polyisobutylene adhesives are weighed in together, then mixed.Subsequently, while stirring, Heptan, Klearol® and Cab-O-Sil® are added.Stirring is continued until a homogenous mass is obtained.

The mass is applied to a removable layer (“release liner”) as a thinfilm, then the solvents are drawn off at 60° C./20 min and 80° C./5 min.After drying, the laminate is coated with the reservoir layer, whereinthe “intermediate liner” is removed first.

Patches of expedient sizes are punched from the laminate.

Stability Tests

The batches A and B were subjected to stability tests. To this end, thepunched-out TTS were sealed in aluminum foil bags and stored for onemonth at 25° C. and 60% relative humidity; respectively, at 40° C. and75% relative humidity. Afterwards, the extent of the contaminations thatmay have formed due to the degradation of rivastigmine was determined bymeans of HPLC and UV absorption. The results of these tests are compiledin Table 3.

TABLE 3 Contamination Batch 25° C./60% rel. hum. 40° C./75% rel. hum.Storage A RT = 46 min: 0.18% — Initially Total: 0.18% RT = 46 min: 0.22%RT = 46 min: 0.29% 1 month Total: 0.22% Total: 0.29% B RT = 46 min:0.34% RT = 46 min: 0.35% 2 weeks Total: 0.34% Total: 0.35% RT = 46 min:0.36% RT = 46 min: 0.38% 1 month Total: 0.36% Total: 0.38%

The found contamination is indicated by its respective retention time(RT). The percentage amount of contamination is the proportion of thetotal weight of the involved formulations. The lower limit of theindicated measured values RL (Reporting Limit) is 0.1% because allvalues there-below are in the range of measuring inaccuracy.

The results of this study clearly show that the TTS formulationsaccording to the invention demonstrate adequate stability. In allformulation examples, the contamination RT=46 min after one month at 40°C. and 75% relative humidity is below 0.4%.

Example 2 Preparation of Different Formulations

Two different batches of TTS formulations containing rivastigmine basewere prepared. Acrylate vinyl-acetate copolymer was used asmatrix-forming polymer for the reservoir. An overview as to thecomponents of the different batches is shown in Table 4.

TABLE 4 Composition of Batches 179/181 and 179/182: Batch Composition179/181 Reservoir: 25% rivastigmine base 75% Duro-Tak ® 87-4098 Adhesivelayer: 30% Pionier ® 7028P (Hansen & Rosenthal) 0.5% Cab-O-Sil ® 69.5%Oppanol ® B10 SFN/B50 SF (4/6) 179/182 Reservoir: 25% rivastigmine base75% Duro-Tak ® 87-4098 Adhesive layer: 35% paraffin, thin-fluid (Merck)0.5% Cab-O-Sil ® 64.5% Oppanol ® B10 SFN/B50 SF (4/6)

The components used in the batches can be described in more detail asfollows:

TABLE 5 Component Overview of Formulation Examples Component NameChemical Description Function Duro-Tak ® Acrylate/vinyl-acetat Matrix87-4098 copolymer polymer Cab-O-Sil ® Pyrogenic silicone dioxideGelatinizing agent Pionier ® Light mineral oil (paraffinum Emollient7028P perliquidum) Oppanol ® B10 Polyisobutylene Contact SFN (M_(v) =ca. 4 × 10⁴ g/mol) adhesive Oppanol ® B50 Polyisobutylene Contact SF(M_(v) = ca. 4 × 10⁵ g/mol) adhesive

Preparation Method 1. Preparation of the Reservoir Layer

The acrylate-vinyl acetate adhesive is provided and rivastigmine andethyl acetate are weighed in. Then the components are mixed in asufficient quantity of ethyl acetate by means of an agitator until aspreadable, homogenous coating mass is achieved.

The homogenous coating mass is applied to a siliconized film(“intermediate liner”) as a thin film. The matrix film is dried at 60°C./20 min and 80° C./5 min, then coated with a cover layer of PET.

2. Preparation of the Adhesive Layer and the Total Laminate

The polyisobutylene adhesives are weighed in together, then mixed.Subsequently, while stirring, heptane, Pionier® 7028P/paraffin oil (thinliquid) and Cab-O-Sil® are added. Stirring is continued until ahomogenous mass is obtained.

The mass is applied to a removable layer (“release liner”) as a thinfilm, then the solvents are drawn off at 60° C./20 min and 80° C./5 min.After drying, the laminate is coated with the reservoir layer, whereinthe “intermediate liner” is removed first. Patches of expedient sizesare punched from the laminate.

Stability Tests

Batches A and B were subjected to stability tests. In this context, thepunched-out TTS were sealed in aluminum foil bags and stored for onemonth at 25° C. and 60% relative humidity; respectively, at 40° C. and75% relative humidity. Afterwards, the extent of contamination that mayhave formed due to the degradation of rivastigmine was determined bymeans of HPLC and UV absorption. The results of these tests are compiledin Tables 6 and 7.

[Glossary for tables 6 and 7]

Table 6: Contaminations in Formulation 179/181

Initial=initiallyMonat=monthMonate=months

Table 7: Contaminations in Formulation 179/182

Initial=initiallyMonat=monthMonate=months

TABLE 6 Verunreinigungen in Formulierung 179/181 1 Monat 3 Monate 6Monate Initial 25° C. 40° C. 5° C. 25° C. 40° C. 25° C. 40° C. Imp 1:<RL Imp 1: <RL Imp 1: <RL Imp 1: <RL Imp 1: <RL Imp 1: <RL Imp 1: <RLImp 1: <RL Imp 4: <RL Imp 4: <RL Imp 4: 0.13% Imp 4: 0.12% Imp 4: 0.12%Imp 4: 0.25% Imp 4: 0.14% Imp 4: 0.30% Imp 5: <RL Imp 5: 0.11% Imp 5:0.14% Imp 5: 0.17% Imp 5: 0.17% Imp 5: 0.26% Imp 5: 0.18% Imp 5: 0.36%Total: <RL Total: 0.11% Total: 0.27% Total: 0.29% Total: 0.29% Total:0.51% Total: 0.32% Total: 0.66%

TABLE 7 Verunreinigungen in Formulierung 179/182 1 Monat 3 Monate 6Monate Initial 25° C. 40° C. 5° C. 25° C. 40° C. 25° C. 40° C. Imp 1:<RL Imp 1: <RL Imp 1: <RL Imp 1: <RL Imp 1: <RL Imp 1: <RL Imp 1: <RLImp 1: <RL Imp 4: <RL Imp 4: <RL Imp 4: 0.16% Imp 4: <RL Imp 4: 0.13%Imp 4: 0.25% Imp 4: 0.14% Imp 4: 0.36% Imp 5: <RL Imp 5: 0.11% Imp 5:0.17% Imp 5: 0.13% Imp 5: 0.15% Imp 5: 0.28% Imp 5: 0.18% Imp 5: 0.41%Total: <RL Total: 0.11% Total: 0.33% Total: 0.13% Total: 0.28% Total:0.53% Total: 0.32% Total: 0.77%

The quantity information provided as a percentage of the contaminationis the proportion of the desired content of active substance in theinvolved formulations. The lower limit of the measuring values(reporting limit) of the individual contaminations is 0.1% because anyvalues below are in the range of measuring inaccuracy. Aside from thecontaminations as reported in Tables 6 and 7, no further contaminationwas detected above the “reporting limit” of 0.1%.

The results of this study clearly show that the TTS formulationsdemonstrate adequate stability.

The present invention refers, among others aspects, to the followingsubject-matters (1) to (17):

(1) A transdermal therapeutic system for administering of rivastigminecomprising the following components:

-   -   a) a cover layer,    -   b) a reservoir present on the cover layer, comprising a polymer        matrix with the embedded active substance, and wherein the        active substance is rivastigmine or a physiologically compatible        salt, hydrate, solvate or derivatives thereof,    -   c) an adhesive layer on the reservoir comprising a first        polyisobutylene polymer of a mean molecular weight between        30,000 g/mol and 100,000 g/mol and a second polyisobutylene        polymer of a mean molecular weight between 300,000 g/mol and        500,000 g/mol, and    -   d) a removable layer present on the adhesive layer,        characterized in that the polymer matrix of the reservoir        includes neither hydroxyl groups nor carboxyl groups.        (2) The transdermal therapeutic system according to        subject-matter (1) wherein it does not contain any antioxidants.        (3) The transdermal therapeutic system according to        subject-matter (1) or (2) wherein the reservoir contains 20 to        30 weight % active substance and 70 to 80 weight % polymer        matrix in relation to the total weight of the reservoir.        (4) The transdermal therapeutic system according to any one of        the subject-matters (1) to (3) wherein the adhesive layer        additionally contains a gelatinizing agent and an emollient.        (5) The transdermal therapeutic system according to        subject-matter (4) wherein the adhesive layer contains 60.0 to        74.9 weight % contact adhesive, 0.1 to 2.0 weight % gelatinizing        agent and 25 to 39.9 weight % emollient in relation to the total        weight of the adhesive layer.        (6) The transdermal therapeutic system according to any one of        the subject-matters (1) to (5) wherein the polymer matrix        comprises at least one polymer and/or copolymer selected from        the group consisting of polyacrylates, acrylate-vinyl acetate        copolymers, polyisobutylene, styrene-butadiene copolymers and        mixtures thereof.        (7) The transdermal therapeutic system according to any one of        the subject-matters (1) to (6) wherein the first polyisobutylene        polymer has a mean molecular weight M_(V) of approximately        40,000 g/mol, and the second polyisobutylene polymer has a mean        molecular weight M_(V) of approximately 40,000 g/mol.        (8) The transdermal therapeutic system according to any one of        the subject-matters (1) to (7) wherein the weight ratio of the        first polyisobutylene polymer in relation to the second        polyisobutylene polymer is approximately 4:6.        (9) The transdermal therapeutic system according to any one of        the subject-matters (1) to (8) wherein the gelatinizing agent        SiO₂ is present in highly dispersed form or in form of pyrogenic        silicic acid.        (10) The transdermal therapeutic system according to any one of        the subject-matters (4) to (9) wherein the emollient is        paraffin, neutral oil, mineral oil or polybutene or a mixture        thereof.        (11) The transdermal therapeutic system according to any one of        the subject-matters (1) to (10) wherein the area of the adhesive        layer corresponds to the area of the reservoir.        (12) A transdermal therapeutic system for administering an        active substance through the skin comprising:    -   a) a cover layer;    -   b) a reservoir located on the cover layer containing 20 to 30        weight % active substance and 70 to 80% polymer matrix in        relation to the total weight of the reservoir, and wherein the        polymer matrix consists essentially of an acrylate-vinyl acetate        copolymer without hydroxyl groups and without carboxyl groups;    -   c) an adhesive layer located on the reservoir that comprises 0.1        to 1 weight % silicone dioxide, 25 to 39.9 weight % paraffinum        perliquidum (Ph. Eur.) and 60 to 79.9 weight % of a mixture of a        polyisobutylene of a mean molecular weight M_(V) of        approximately 40,000 g/mol and polyisobutylene of a mean        molecular weight M_(V) of approximately 400,000 g/mol; and    -   d) a removable layer located on the adhesive layer.        (13) A method for preparing a transdermal therapeutic system        according to any one of the subject-matters (1) to (12)        comprising    -   i) preparing a component containing the reservoir made up of the        cover layer and the reservoir, which is located on the side of        the cover layer that is intended as the side to be directed        toward the skin;    -   ii) preparing a component containing the adhesive layer made up        of the removable layer and the adhesive layer located on the        removable layer; and    -   iii) laminating to combine the components from i) and ii) so        that in the end, in the cross-section of the completed TTS, the        cover and removable layers constitute the outermost, opposite        layers.        (14) The method according to subject-matter (13) comprising    -   i) applying, with drying, if necessary, a film of a composition        constituting the reservoir, if necessary, in form of a solution        or dispersion in an expedient medium to the side of the cover        layer that is to be directed toward the skin;    -   ii) applying, with subsequent drying, if necessary, a film of a        composition constituting the adhesive layer, if necessary, in        the form of a solution or dispersion in an expedient medium, to        the removable layer; and    -   iii) laminating together the components from i) and ii), if        necessary, removing the liner in order for the cover layer and        the removable layer to constitute in the cross-section of the        completed TTS the outermost, opposite layers.        (15) The method according to subject-matter (13) comprising    -   i) applying, with drying, if necessary, a film of a composition        constituting the reservoir, if necessary, in form of a solution        or dispersion in an expedient medium to the side of the cover        layer that is to be directed toward the skin and, if necessary,        coating with a siliconized removable film (liner);    -   ii) applying, with subsequent drying, if necessary, a film of a        composition constituting the adhesive layer, if necessary, in        the form of a solution or dispersion in an expedient medium, to        the removable layer; and    -   iii) laminating together the components from i) and ii), if        necessary, removing the liner in order for the cover layer and        the removable layer to constitute in the cross-section of the        completed TTS the outermost, opposite layers.        (16) The use of a polymer or copolymer that contains neither        hydroxyl groups nor carboxyl groups selected from the group        consisting of polyacrylates, acrylate-vinyl acetate copolymers,        polyisobutylene and styrene-butadiene copolymers for preparing        transdermal therapeutic systems containing rivastigmine.        (17) The transdermal therapeutic system according to any one of        the subject-matters (1) to (12) for treating Alzheimer's and        Parkinson's dementia.

The subject-matters (1) to (17) can be combined with other embodiedexamples as described in the present application.

1. A method for preparing a transdermal therapeutic system containingrivastigmine, comprising embedding the rivastigmine or a physiologicallycompatible salt, hydrate, solvate or derivative thereof in a polymermatrix comprising a polymer and/or copolymer or mixture thereof, whereinsaid polymer and/or copolymer or mixture thereof contains essentiallyneither free hydroxyl groups nor free carboxyl groups.
 2. The method ofclaim 1 wherein said step of embedding results in stabilizing therivastigmine in the transdermal therapeutic system.
 3. The method ofclaim 1 wherein said step of embedding results in reducing thebreak-down of the rivastigmine in the transdermal therapeutic system. 4.The method of claim 1, wherein the polymer or copolymer is selected fromthe group consisting of polyacrylates, acrylate-vinyl acetatecopolymers, polyisobutylene and styrene-butadiene copolymers.
 5. Themethod of claim 2, wherein the polymer or copolymer is selected from thegroup consisting of polyacrylates, acrylate-vinyl acetate copolymers,polyisobutylene and styrene-butadiene copolymers.
 6. The method of claim3, wherein the polymer or copolymer is selected from the groupconsisting of polyacrylates, acrylate-vinyl acetate copolymers,polyisobutylene and styrene-butadiene copolymers.
 7. The method of claim1, wherein the transdermal therapeutic system contains no antioxidants.8. The method of claim 2, wherein the transdermal therapeutic systemcontains substantially no antioxidants.
 9. The method of claim 3,wherein the transdermal therapeutic system contains substantially noantioxidants.
 10. The method of claim 4, wherein the transdermaltherapeutic system contains substantially no antioxidants.
 11. Themethod of any one of claims 1 to 10, wherein the transdermal therapeuticsystem comprises: a) a cover layer, b) a reservoir present on the coverlayer, comprising the polymer matrix comprising said polymer orcopolymer, c) an adhesive layer on the reservoir comprising a contactadhesive, and d) a removable layer present on the adhesive layer. 12.The method of claim 11, wherein the reservoir contains 20 to 30 weight %rivastigmine and 70 to 80 weight % polymer matrix in relation to thetotal weight of the reservoir.
 13. The method of claim 11, wherein theadhesive layer additionally contains a gelatinizing agent and anemollient.
 14. The method of claim 11, wherein the adhesive layercontains 60.0 to 74.9 weight % contact adhesive, 0.1 to 2.0 weight %gelatinizing agent and 25 to 39.9 weight % emollient in relation to thetotal weight of the adhesive layer.
 15. The method of claim 11, whereinthe contact adhesive is polyisobutylene.
 16. The method of claim 15,wherein the polyisobutylene is a mixture of two polyisobutylene polymersof different molecular weights.
 17. The method of claim 16, wherein thefirst polyisobutylene polymer has a mean molecular weight M_(V) ofapproximately 40,000 g/mol, and the second polyisobutylene polymer has amean molecular weight M_(V) of approximately 400,000 g/mol.
 18. Themethod of claim 16 or 17, wherein the weight ratio of the firstpolyisobutylene polymer in relation to the second polyisobutylenepolymer is approximately 4:6.
 19. The method of claim 13, wherein thegelatinizing agent is SiO₂ in a highly dispersed form or in the form ofpyrogenic silicic acid.
 20. The method of claim 13, wherein theemollient is paraffin, neutral oil, mineral oil or a mixture thereof.21. A polymer matrix containing rivastigmine, wherein the rivastigmineor a physiologically compatible salt, hydrate, solvate or derivativethereof is embedded in a polymer matrix comprising a polymer and/orcopolymer or mixture thereof and wherein said polymer and/or copolymeror mixture thereof contains essentially neither free hydroxyl groups norfree carboxyl groups.
 22. A transdermal therapeutic system containingrivastigmine, wherein the rivastigmine or a physiologically compatiblesalt, hydrate, solvate or derivative thereof is embedded in a polymermatrix comprising polymer and/or copolymer or mixture thereof andwherein said polymer and/or copolymer or mixture thereof containsessentially neither free hydroxyl groups nor free carboxyl groups.